Compositions and methods for modulating at2r activity

Abstract

New polypeptide agonists of AT2R are disclosed, as well as pharmaceutical compositions comprising the agonists, methods of their use in the treatment of diseases, conditions or disorders characterized by insufficient AT2R activity or excessive AT1R activity, and methods of their use as laboratory reagents for research purposes.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of PCT / US15 / 061597, entitled “Compositions and Methods for Modulating AT2R Activity”, and filed on Nov. 19, 2015, which claims priority to U.S. Provisional application 62 / 081,839, entitled “Compositions and Methods for Modulating AT2R Activity”, and filed on Nov. 19, 2014, both of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The invention relates to the fields of molecular biology and biochemistry, and in particular to the development of pharmaceuticals for the modulation of the activity of the Angiotensin II Type 2 Receptor (AT2R).BACKGROUND[0003]The Angiotensin II Type 2 Receptor AT2R is a member of the anti-inflammatory / vasodilative branch of the renin-angiotensin system (RAS). AT2R-activation ameliorates cardiovascular diseases and stroke, attenuates cancers and exerts a neuroprotective role (1-17).[0004]AT2R is a transmembrane receptor protein comprising a...

AI Technical Summary

Benefits of technology

The present invention is based on the discovery of small peptides that can activate the Angiotensin 2 Type II Receptor (AT2R). These peptides can be used as research, diagnostic, and therapeutic reagents. They can be administered to mammals to treat diseases and disorders associated with insufficient or excessive activity of the AT2R. The peptides are polypeptides or polypeptide derivatives with a specific sequence. The invention provides pharmaceutical compositions containing the peptides and methods for their use in research and treatment. The peptides can also be used to control the activity of other receptors and pathways downstream of the AT2R.

Problems solved by technology

Even though AT2R belongs to the GPCR family of proteins, its signaling mechanisms are atypical and remain elusive.

However, evidence from randomized clinical trials such as the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) shows that dual RAS blockade was not beneficial compared to monotherapy in preventing serious outcomes in patients with known vascular disease or diabetes with end-organ damage (56-58).

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